This invention relates generally to novel amide derivatives as inhibitors of matrix metalloproteinases, TNF-xcex1, and aggrecanase, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as xcex1-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J Bone Joint Surg 1970, 52A, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 1983, 26, 63-68 and Ibid. 1984, 27, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander et al. Arthritis Rheum. 1993, 36, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 1990, 25, 175-184, AP, San Diego).
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander et al. Arthritis Rheum. 1993, 36, 1214-22) and Crohn""s disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-a from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechanisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
WO95/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production. 
EP 574,758 A1 depicts hydroxamic acid derivatives as collagenase inhibitors having the general formula: 
GB 2,268,934 A and WO94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
WO97/08133 portrays compounds, for treating inflammatory diseases, of the formula: 
wherein Ring M is an aromatic ring, cycloalkylene or a divalent heterocycle. Compounds of this sort art not considered to be included in the present invention.
The compounds of the current invention act as inhibitors of MMPs, aggrecanase and/or TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Accordingly, one object of the present invention is to provide novel amides which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, C, R1, R2, R3, and R4 are defined below, are effective metalloprotease inhibitors.
Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from COR5, xe2x80x94CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94NHRa, xe2x80x94N(OH)COR5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, SN2H2Ra, xe2x80x94S(O)(xe2x95x90NH)Ra, xe2x80x94S(xe2x95x90NH)2Ra, PO(OH)2, and PO(OH)NHRa;
R1 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rQ, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rNRaC(O)(CRRxe2x80x2)rNHQ, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)ORa, and (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)(CRRxe2x80x2)rNHC(O)ORa;
alternatively, R1 and Rbxe2x80x2 taken together with the CR2-N to which they are attached form a 4-8 membered cyclic amine containing from 0-1 double bonds, O-1 S(O)p, O-1 oxygen atoms, and 0-1 NRa, and substituted with 0-1 groups selected from OH and xe2x95x90O and is substituted with 0-3 Rb;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rxe2x80x2, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
alternatively, R and Rxe2x80x2 together with the carbon to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group;
Q, at each occurence, is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from H, C1-10 alkylene-H, C2-10 alkenylene-H, C2-10 alkynylene-H, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94H, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94H;
R3 is Uxe2x80x94Xxe2x80x94Y Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94X1xe2x80x94Za;
U is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Y is absent or selected from O, NRa, S(O)p, S(O)pNRa, C(O)NRa, and C(O), provided that when U and Y are present, X is present;
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rd and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
Ua is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Ya is absent or selected from O, NRa, S(O)p, S(O)pNRa, C(O)NRa, and C(O), provided that when Ua and Ya are present, Xa is present;
X1 is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Za is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rd and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R4 is selected from H, Qxe2x80x2, C1-10 alkylene-Qxe2x80x2, C2-10 alkenylene-Qxe2x80x2, C2-10 alkynylene-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rQxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)r-Qxe2x80x2,(CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)r-Qxe2x80x2and (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rQxe2x80x2;
R4a is selected from H, C1-6 alkyl, xe2x80x94C1-6 alkyl-phenyl, and phenyl; alternatively, R4 and R4a, together with the carbon to which they are attached, combine to form a 3-8 membered carbocyclic ring substituted with 0-3 Rb or a 3-8 membered heterocyclic ring containing from 1-3 heteroatoms selected from N, 0, and S(O)p and substituted with 0-3 Rb;
Qxe2x80x2 is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl or benzyl;
Raxe2x80x3, at each occurrence, is independently selected from C1-4 alkyl, phenyl or benzyl; alternatively, Ra and Raxe2x80x2, taken together with the nitrogen to which they are attached form a 4, 5, or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb is selected from H, C1-6 alkyl, phenyl, benzyl, C(O)Ra, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, and S(O)pRaxe2x80x3;
Rbxe2x80x2 is selected from H, Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)r-Q, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)r-Q;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, (CRRxe2x80x2)sO(CRRxe2x80x2)sxe2x80x2, Rcxe2x80x2, (CRRxe2x80x2)sS(O)p(CRRxe2x80x2)sxe2x80x2Rcxe2x80x2, (CRRxe2x80x2)sNRa(CRRxe2x80x2)sxe2x80x2Rcxe2x80x2, C3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rcxe2x80x2, at each occurrence, is independently selected from phenyl substituted with 0-3 Rb, biphenyl substituted with 0-2 Rb, naphthyl substituted with 0-3 Rb and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, NRaC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5, at each occurrence, is selected from H, C1-10 alkyl substituted with 0-2 Re, and C1-8 alkyl substituted with 0-2 Rf;
Re, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRaxe2x80x3, CF3, and CF2CF3;
Rf, at each occurrence, is selected from phenyl substituted with 0-2 Re and biphenyl substituted with 0-2 Re;
R6 at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a,xe2x80x94CH(R8)OC(xe2x95x90O)R9,xe2x80x94CH(R8)OC(xe2x95x90O)OR9, and 
R7 is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Rg, C3-8 cycloalkyl substituted with 1-2 Rg, phenyl substituted with 0-2 Re;
Rg, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Re;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and,
s, at each occurrence, is selected from 0, 1, 2, and 3.
In a preferred embodiment, the present invention provides compounds, wherein:
A is selected from COR5, xe2x80x94CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
R1 is selected from H, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CH2)rxe2x80x2O(CH2)r-Q, (CH2)rxe2x80x2NRa(CH2)r-Q, (CH2)rxe2x80x2C(O)(CH2)r-Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)r-Q, (CH2)rxe2x80x2C(O)NRa(CH2)r-Q, (CH2)rxe2x80x2NRaC(O)(CH2)r-Q, (CH2)rxe2x80x2OC(O)NRa(CH2)r-Q, (CH2)rxe2x80x2NRaC(O)O(CH2)r-Q, (CH2)rxe2x80x2NRaC(O)NRa(CH2)r-Q, (CH2)rxe2x80x2S(O)p(CH2)r-Q, (CH2)rxe2x80x2SO2NRa(CH2)r-Q, (CH2)rxe2x80x2NRaSO2(CH2)r-Q, and (CH2)rxe2x80x2NRaSO2NRa(CH2)r-Q;
Q is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from H, C1-6 alkylene-H, C2-6 alkenylene-H, C2-6 alkynylene-H, (CH2)rxe2x80x2O(CH2)rxe2x80x94H, (CH2)rxe2x80x2NRa(CH2)rxe2x80x94H, (CH2)rxe2x80x2C(O)(CH2)rxe2x80x94H (CH2)rxe2x80x2C(O)NRa(CH2)rxe2x80x94H, (CH2)rxe2x80x2NRaC(O)(CH2)rxe2x80x94H, (CH2) rxe2x80x2SO2NRa(CH2)rxe2x80x94H, and (CH2)rxe2x80x2NRaSO2(CH2)rxe2x80x94H;
U is absent or is selected from: O, NRa, C(O), C(O)NRa, and NRaC(O);
X is absent or selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene;
Y is absent or selected from O, NRa, C(O)NRa, and C(O), provided that when U and Y are present, X is present;
Z is absent or selected from a C3-10 carbocyclic residue substituted with 0-5 Rd and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
Ua is absent or is selected from: O, NRa, C(O), C(O)NRa, and NRaC(O);
Xa is absent or selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene;
Ya is absent or selected from O, NRa, C(O)NRa, and C(O), provided that when Ua and Ya are present, Xa is present;
X1 is absent or selected from C1-6 alkylene, C2-6 alkenylene, and C2-6 alkynylene;
Za is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rd and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R4 is selected from H, Qxe2x80x2, C1-5 alkylene-Qxe2x80x2, C2-5 alkenylene-Qxe2x80x2, C2-5 alkynylene-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x2-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O) (CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)r-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2S (O)p(CRRxe2x80x2)r-Qxe2x80x2, and (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x2-Qxe2x80x2;
R4a is selected from H, C1-4 alkyl, xe2x80x94C1-4 alkyl-phenyl, and phenyl;
alternatively, R4 and R4a, together with the carbon to which they are attached, combine to form a 3-6 membered carbocyclic ring substituted with 0-3 Rb or a 3-6 membered heterocyclic ring containing from 1-3 heteroatoms selected from N, O, and S(O)p and substituted with 0-3 Rb;
Qxe2x80x2 is selected from H, phenyl substituted with 0-3 Rb and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Rbxe2x80x2 is selected from H, Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rC(O)(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rC(O)O(CRRxe2x80x2)r-Q, (CRRxe2x80x2)rC(O)NRa(CRRxe2x80x2)rxe2x80x2-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x2-Q, and (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x2-Q;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C5-10 carbocyclic residue and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2OS(O)pRaxe2x80x3, CF3, CF2CF3, C3-10 carbocyclic residue and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5; and,
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5.
In a more preferred embodiment, the present invention provides compounds, wherein:
A is selected from xe2x80x94CO2H, xe2x80x94CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
Q is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is selected from H, CH3, and CH2CH3;
U is absent;
X is absent or is C1-3 alkylene;
Y is absent;
Z is absent or is selected from a C6-10 aryl group substituted with 0-3 Rd and a 5-10 membered heteroaryl group containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
Ua is absent;
Xa is absent or selected from C1-3 alkylene and C2-3 alkenylene;
Ya is absent or selected from O and NRa;
X1 is absent or is C1-3 alkylene;
Za is selected from H, a C1-10 carbocyclic residue substituted with 0-5 Rd and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R4 is selected from H, C1-5 alkylene-Qxe2x80x2, (CH2)rxe2x80x2O(CH2)r-Q, and (CH2)rNRa(CH2)r-Qxe2x80x2;
R4a is selected from H and C1-4 alkyl; alternatively, R4 and R4a, together with the carbon to which they are attached, combine to form a 3-6 membered carbocyclic ring substituted with 0-3 Rb;
Qxe2x80x2 is H or phenyl substituted with 0-3 Rb;
Rbxe2x80x2 is selected from H, C1-4 alkylene-Q, C2-4 alkenylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x2-Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x2-Q, (CRRxe2x80x2)rC(O)(CRRxe2x80x2)rxe2x80x2-Q, (CRRxe2x80x2)rC(O)NRa(CRRxe2x80x2)rxe2x80x2-Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x2-Q;
r, at each occurrence, is selected from 0, 1, 2, and 3; and,
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, and 3.
In an even more preferred embodiment, the present invention provides compounds, wherein:
A is selected from xe2x80x94CO2H, xe2x80x94CONHOH, and xe2x80x94CONHOR5;
R1 is selected from H, C1-6 alkylene-Q, (CH2)rxe2x80x2O(CH2)rxe2x80x2-Q, (CH2)rxe2x80x2NRa(CH2)rxe2x80x2-Q, (CH2)rxe2x80x2C(O)(CH2)rxe2x80x2-Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x2-Q, (CH2)rxe2x80x2C(O)NRa(CH2)rxe2x80x2-Q, and (CH2)rxe2x80x2NRaC(O)(CH2)rxe2x80x2-Q;
Q is selected from H, a C5-10 carbocyclic residue substituted with 0-3 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R2 is H;
X is absent or is CH2 or CH2CH2;
Z is absent or is selected from phenyl substituted with 0-3 Rd and a 5-6 membered heteroaryl group containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rd;
Xa is absent or is CH2 or CH2CH2;
Ya is absent or O;
X1 is absent or is CH2 or CH2CH2;
Za is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rd and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rd;
R4 is selected from H, OH, NH2, CH3, CH2OH, and CH2NH2;
R4a is selected from H, CH3 and CH2CH3;
alternatively, R4 and R4a, together with the carbon to which they are attached, combine to form a 3-5 membered carbocyclic ring substituted with 0-2 Rb;
Rbxe2x80x2 is selected from H, C1-2 alkyl-Q, (CRRxe2x80x2)rxe2x80x2NHRa, and (CRRxe2x80x2)rC(O)NHRa;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C5-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, RaNC(O)NRaRaxe2x80x2, OC(O)NRaRaxe2x80x2, RaNC(O)O, S(O)2NRaRaxe2x80x2, NRaS(O)2Raxe2x80x3, NRaS(O)2NRaRaxe2x80x2, OS(O)2NRaRaxe2x80x2, NRaS(O)2O, S(O)pRaxe2x80x3, CF3, CF2CF3, C3-6 carbocyclic residue and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; and,
r, at each occurrence, is selected from 0, 1, and 2;
rxe2x80x2, at each occurrence, is selected from 1, and 2; and,
s, at each occurrence, is selected from 0 and 1.
In a further preferred embodiment, the present invention provides novel compounds of formula Ia, wherein: 
In a further preferred embodiment, the present invention provides novel compounds of formula Ib, wherein: 
and n is selected from 1, 2, and 3.
In another preferred embodiment, the present invention provides novel compounds is selected from:
(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methylphenyl)cyclopropanecarboxamide;
(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide;
(R)-N-[1-[(hydroxyamino)carbonyl]-3-(methylthio)propyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide;
(R)-N-[1-[(hydroxyamino)carbonyl]-3-(methylsulfonyl)propyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide;
N-[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]-N,xcex1,xcex1-trimethylbenzeneacetamide;
(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methyl-1-phenylcyclopropanecarboxamide;
(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methyl-1-(4-methylphenyl)cyclopropanecarboxamide;
(R)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-1-(4-methoxyphenyl)-N-methylcyclopropanecarboxamide;
(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopropanecarboxamide;
(R)-1-(2,4-dichlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopropanecarboxamide;
(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclobutanecarboxamide;
(R)-1-(4-chlorophenyl)-N-[1-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylcyclopentanecarboxamide;
xcex1-(R)-hydroxy-N-[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]-N-methylbenzeneacetamide;
1,1-dimethylethyl [2-[[1-(R)-[(hydroxyamino)carbonyl]-2-methylpropyl]methylamino]-2-oxo-1-phenylethyl]carbamate;
1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2-piperidinecarboxamide;
1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}-N-hydroxy-2-pyrrolidinecarboxamide;
(2R)-N-hydroxy-2-[[(4-methoxyphenyl)acetyl](methyl)amino]-3-methylbutanamide;
1-{4-[(2,4-dimethylbenzyl)oxyphenyl}-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methylcyclopropanecarboxamide;
(2S)-N-hydroxy-2-[[(4-methoxyphenyl)acetyl](methyl)amino]propanamide;
N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(2-naphthylmethoxy)phenyl]cyclopropanecarboxamide;
N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(4-pyridinylmethoxy)phenyl]cyclopropanecarboxamide;
(2R)-2-[{[4-(benzyloxy)phenyl]acetyl}(methyl)amino]-N-hydroxy-3-methylbutanamide;
(2R)-2-[({4-[(3,5-dimethylbenzyl)oxy]phenyl}acetyl)(methyl)amino]-N-hydroxy-3-methylbutanamide;
(2R)-2-[{[4-(1H-1,2,3-benzotriazol-1-ylmethoxy)phenyl]acetyl}(methyl)amino]-N-hydroxy-3-methylbutanamide;
N-[(1S)-2-(hydroxyamino)1-methyl-2-oxoethyl]-N-methyl-1-{4-[(3-phenyl-5-isoxazolyl)methoxy]phenyl}cyclopropanecarboxamide;
N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-[4-(2-propynyloxy)phenyl]cyclopropanecarboxamide;
1-(4-{[3-(4-fluorophenyl)-5-isoxazolyl]methoxy}phenyl)-N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methylcyclopropanecarboxamide;
N-[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl]-N-methyl-1-{4-[(3-propyl-5-isoxazolyl)methoxy]phenyl}cyclopropanecarboxamide;
N-{(1S)-1-[(hydroxyamino)carbonyl]-3-methylbutyl}-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-N-propylcyclopropanecarboxamide;
N-[3-(cyclopentylamino)propyl]-N-{(1S)-1-[(hydroxyamino)carbonyl]-3-methylbutyl}-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}cyclopropanecarboxamide;
tert-butyl (1S)-1-[4-(benzyloxy)phenyl]-2-[[(1S)-2-(hydroxyamino)-1-methyl-2-oxoethyl](methyl)amino]-2-oxoethylcarbamate;
(1S)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)cyclopentanecarboxamide; (1R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)cyclopentanecarboxamide;
(3S)-N-hydroxy-2,2-dimethyl-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-3-thiomorpholinecarboxamide;
(2R)-N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperidinecarboxamide;
tert-butyl 3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1-piperazinecarboxylate;
N-hydroxy-1-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-2-piperazinecarboxamide;
benzyl (3R)-3-[(hydroxyamino)carbonyl]-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)tetrahydro-1 (2H)-pyridazinecarboxylate;
(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)hexahydro-3-pyridazinecarboxamide;
(3R)-N-hydroxy-2-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide;
2-((R/S)-2-phenylbutyramido)-N-hydroxy-(R)-propionamide;
2-((R/S)-xcex1-Methyl-4-isobutylphenylacetamido)-N-hydroxy-(R)-propionamide;
2-((R/S)-2-Fluoro-xcex1-methyl-4-biphenylacetamido)-N-hydroxy-(R)-propionamide;
2-[N-Methyl-N-((R/S)-xcex1-Methyl-4-benzyloxyphenylacetyl amino)]-N-hydroxy-(R)-propionamide;
2-{N-Methyl-N-[(R/S)-xcex1-methyl-4-(3,5-dimethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide;
2-{N-Methyl-N-[(R/S)-xcex1-methyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide.;
2-{N-Methyl-N-[(R/S)-xcex1-(methylaminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide.;
2-{N-Methyl-N-[(R/S)-xcex1-(aminocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide.;
2-{N-Methyl-N-[(R/S)-xcex1-(1-piperazinocarbonylmethyl)-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-N-hydroxy-(R)-propionamide.;
(2R)-2-[(amino {4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-N-hydroxy-4-methylpentanamide; and,
2-[(amino {4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)amino]-N-hydroxy-2-methylpropanamide
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel compounds of formula (I) for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of formula (I) for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkyl xe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10O alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynyl xe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term xe2x80x9camino acidxe2x80x9d as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5xe2x80x2-triiodothyronine, and 3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, 3-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a MMP, TNF, aggrecanase, or a combination thereof in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul 1984, 22, 27-55, occurs when the effect (in this case, inhibition of a desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of acetamides of formula 6 are prepared by the method outlined in Scheme 1. Reaction of BOC-protected D-amino acid 1 with O-benzylhydroxylamine and acid hydrolysis gives amine 3. Coupling of 3 with acid 4 followed by hydrogenolysis using palladium on barium sulfate as a catalyst provides the desired hydroxamic acid 6. 
A series of cyclopropanecarboxamides and cyclobutanecarboxamides of formula are prepared by the method outlined in Scheme 2. Mono-alkylation of xcex1-substituted methyl acetate 7 with ethylene bromide and 1,3-dibromopropane, followed by treatment with sodium hydride in DMSO provides cyclopropanecarboxylates and cyclobutanecarboxylates, respectively. Hydrolysis of 9 gives the corresponding acid 10. This protocol allows the preparation of 10 with wide range of R3 group.
Many of the requisite D-amino acid methyl ester 11 are commercially available or are prepared from commercial material by simple protecting group manipulations. Others are synthesized using Myers method from glycine (Myers, A. G.; Gleason, J. L.; Yoon, T. J Am. Chem. Soc. 1995, 117, 8488), using Mitsunobu conditions from serine (Cherney, R. J.; Wang, L. J Org. Chem. 1996, 61, 2544), or using Evans electrophilic azidations from carboxylic acids (Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J Am. Chem. Soc. 1990, 112, 4011).
Coupling of 10 and 11 with HATU provides 12. At this point, Rbbxe2x80x2 group is introduced by alkylation with Rbxe2x80x2-X under basic conditions. Hydrolysis and coupling with hydroxylamine then complete the synthesis. This synthetic scheme is flexible and allows independent incorporation of various R1, Rbxe2x80x2 and R3 groups during the synthesis. 
A series of phenylacetamides of formula 18 are prepared following the sequence outlined in Scheme 3. The starting point for the synthesis is benzyloxyphenylacetamide 13, an intermediate from Scheme 2. Deprotection of benzyl group and reaction with triflic anhydride provides triflate 17. Palladium-mediated coupling of 17 under Stille or Suzuki conditions provides 18. Alternatively, 17 reacts with lower or higher-order cuprates to give 18. Ester 18 is then converted to the corresponding hydroxamic acid under standard conditions. 
Another series of phenylacetamides of formula 19 are prepared following the sequence outlined in Scheme 4. Alkylation of phenol 16 with R3xe2x80x2-X yields ester 19. 19 is then converted to the corresponding hydroxamic acid under standard conditions. 
Another series of phenylacetamides of formula 22 are prepared following the sequence outlined in Scheme 5. Starting from 13 when R3 is (p-methoxyphenyl)methoxymethylphenyl group, DDQ oxidation removes the p-methoxybenzyl group. Alcohol 20 is then converted to bromide 21. Alkylation of 21 with R3xe2x80x2xe2x80x94OH yields 22. Ester 22 is converted to the corresponding hydroxamic acid under standard conditions. 
Another series of acetamides of formula 27 with an isoxazole substituent at the a position are prepared using common intermediate 13 following the sequence outlined in Scheme 6. After t-butyl ester hydrolysis, the resultant carboxylic acid 23 is converted to aldehyde 25 by hydroboration and Swern oxidation. Oxime formation, in situ oxidation and [3+2] dipolar cycloaddition with R3xe2x80x2-substituted acetylene provides isoxazole 27. 27 is converted to the corresponding hydroxamic acid under standard conditions. 
Another series of acetamides of formula 30 with an isoxazole substituent at the xcex1 position are prepared using common intermediate 13 following the sequence outlined in Scheme 7. Removal of trimethylsilyl group with NaOH gives terminal acetylene 28. Cycloaddition of 28 with oxime 29 under oxidative conditions provides isoxazole 30. 30 is converted to the corresponding hydroxamic acid under standard conditions. 
Another series of acetamides of formula 34 with an azaoxazole substituent at the xcex1 position are prepared using common intermediate 22 following the sequence outlined in Scheme 8. Acid 22 is first coupled with hydrazine to give 31. Condensation with aldehyde 32 and oxidative cyclization with PhI(OAc)2 providesb azaoxazole 34 (Yang, R. Y.; Dai, L. X. J Org Chem. 1993, 58, 3381). 34 is converted to the corresponding hydroxamic acid under standard conditions. 
Another series of acetamides of formula 39 with an aminothiazole substituent at the xcex1 position are prepared following the sequence outlined in Scheme 9. Partial hydrogenation of acetylene 28 gives olefin 35. 35 is converted to bromoketone 37 by Wacker oxidation and xcex1-bromonation. Treatment of bromoketone 37 with thiourea produces aminothiazole 38 (Markees, D. G.; Burger, A J. Am. Chem. Soc. 1948, 70, 3329.), which is then alkylated with R3xe2x80x2-X. Ester 39 is converted to the corresponding hydroxamic acid under standard conditions. 
Employing the synthetic sequence described as before, a series of acetamides of formula 42 with an imidazole substituent at the xcex1 position are prepared from intermediate 41 (Scheme 10). Likewise, through an intermediacy of 44, ester 43 is converted to a series of thiophene-substituted acetamides 45. 
One diasteriomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.